Alzheimer's disease (AD) risk appears reduced by both NSAIDs and docosahexaenoic acid (DHA). Cognitive deficits in AD are correlated with synaptic deficits, while cognitive deficits in the transgenic mouse models can be rapidly reversed with anti-Abeta antibody or NSAIDs. These effects do not require reduction in insoluble Abeta levels, but may depend on effects on soluble oligomers. Soluble Abeta oligomer-induced LTP and memory deficits are blocked by NSAIDs, and this may be mediated by effects on a Rac-PAK pathway, since it is a known target of oligomer signaling. PAKs are downstream Rac effectors critical for synapse formation, so oligomer-induced defects in PAK signaling may cause synaptic defects in AD. Signaling through the PAK complex, required for synapse formation and survival, is also modulated by DHA. Aged Tg2576 mice were placed on a DHA-depleting "BAD" diet with safflower oil as the major fatty acid. With no evidence for neuron or synaptophysin loss, DHA depletion increased oxidative damage, caspase-cleaved actin and deficits in PSD-95 and the dendritic spine actin-binding protein, drebrin. The effect was transgene-dependent, suggesting that the BAD diet is permissive for a selective APP transgene induced synaptic deficit. Only Tg(+) mice on BAD diet developed major deficits in mRNAs associated with postsynaptic function and memory, including PI3K and PAKS, a gene linked to mental retardation and severe cognitive deficits. We hypothesize that: 1) PAK and PI3-K deficits cause drebrin, PSD-95 and spine loss and cofilin/Hirano pathology and dendritic caspase activation in vitro and in vivo. 2) Adult onset PAK deficits cause cognitive deficits. 3) Chronic Abeta oligomers and DHA depletion limit PAK activation leading to drebrin loss and reduced formation of new spines and synapses in vitro. 4) AD brain has a defective PAK signaling complex related to cognitive deficits. We propose to test these hypotheses in Tg2576, in culture models and in AD brain, focusing on alterations in the PAK kinase signaling complex and sequelae. Understanding dietary fatty acid /Abeta-related PAK complex deficits and downstream synaptic defects will reveal a poorly studied overlap between cognitive deficits in mental retardation syndromes and AD with therapeutic implications.